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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents



ID: 682222.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
Molecular mechanism of SLC5A8 inactivation in breast cancer
Authors:Elangovan, S.; Pathania, R.; Ramachandran, S.; Ananth, S.; Padia, R. N.; Srinivas, S. R.; Babu, E.; Hawthorn, L.; Schoenlein, P. V.; Boettger, T.; Smith, S. B.; Prasad, P. D.; Ganapathy, V.; Thangaraju, M.
Date of Publication (YYYY-MM-DD):2013-10
Journal Abbrev.:Mol Cell Biol
Volume:33
Issue / Number:19
Start Page:3920
End Page:3935
Audience:Not Specified
Abstract / Description:SLC5A8 is a putative tumor suppressor that is inactivated in more than 10 different types of cancer, but neither the oncogenic signaling responsible for SLC5A8 inactivation nor the functional relevance of SLC5A8 loss to tumor growth has been elucidated. Here, we identify oncogenic HRAS (HRAS(G12V)) as a potent mediator of SLC5A8 silencing in human nontransformed normal mammary epithelial cell lines and in mouse mammary tumors through DNMT1. Further, we demonstrate that loss of Slc5a8 increases cancer-initiating stem cell formation and promotes mammary tumorigenesis and lung metastasis in an HRAS-driven murine model of mammary tumors. Mammary-gland-specific overexpression of Slc5a8 (mouse mammary tumor virus-Slc5a8 transgenic mice), as well as induction of endogenous Slc5a8 in mice with inhibitors of DNA methylation, protects against HRAS-driven mammary tumors. Collectively, our results provide the tumor-suppressive role of SLC5A8 and identify the oncogenic HRAS as a mediator of tumor-associated silencing of this tumor suppressor in mammary glands. These findings suggest that pharmacological approaches to reactivate SLC5A8 expression in tumor cells have potential as a novel therapeutic strategy for breast cancer treatment.
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1098-5549 (Electronic) 0270-7306 (Linking) %R 10.1128/MCB.01702-12
URL:http://www.ncbi.nlm.nih.gov/pubmed/23918800
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